In response to the concern about the appropriate diagnosis for children with chronic, severe irritability, we defined a group of children whom we described as having severe mood dysregulation (SMD). These children have extremely severe irritability and symptoms of hyperarousal (the latter being similar to those seen in attention deficit hyperactivity disorder (ADHD)); although they frequently receive the diagnosis of bipolar disorder (BD), they do not indeed meet diagnostic criteria for BD. Our SMD phenotype formed the basis for the new pediatric diagnosis of mood dysregulation disorder with dysphoria (DMDD) in DSM-5. (DMDD differs from SMD primarily in that DMDD does not require the hyperarousal symptoms, related to attention deficit hyperactivity disorder (ADHD)). Since the inception of this project, approximately 270 youth with SMD/DMDD have been recruited into the project. Approximately 25 new patients were recruited this year. It is very important to note that these youth with DMDD suffer very severe psychiatric impairment, and indeed are as ill as youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. Also as noted above, in previous years we demonstrated differences between youth with SMD and those with BD in terms of clinical course, family history, and the brain mechanisms associated with behavioral problems. Thus, while we continue to compare youth with BD and those with severe irritability in terms of mediating brain mechanisms, we have become increasingly interested in the pathophysiology of irritability in its own right. Indeed, irritability is one of the most common presenting symptoms in pediatric psychiatry clinics. As noted above, the construct of irritability is particularly well-suited for a transdiagnostic, translational approach consistent with the Research Domain Criteria (RDoC) approach. Therefore, much of our work this year involved examining irritability, not only within the severely irritable DMDD phenotype, but also in other groups that exhibit considerable irritability, including youth with anxiety disorders, ADHD, or bipolar disorder (BD). Across all groups, we characterize irritability as a continuous variable. A major focus of our neuroimaging work includes the use of frustrating tasks, since a hallmark of irritability is difficulty tolerating frustration. In prior work, we demonstrated behavioral and neural differences between irritable and non-irritable youth while completing a frustrating attentional task. We have improved that paradigm and are now applying it in a large sample of youth with DMDD, BD, ADHD, and/or anxiety disorders, as well as healthy youth. This approach allows us to examine the neural correlates of irritability, operationalized dimensionally, while also comparing DSM-5 diagnostic groups in terms of the brain circuitry engaged during a frustrating task. We have also continued our work comparing the neural circuitry mediating face emotion processing among youth with DMDD, BD, and healthy youth. As with the frustration work, we now incorporate a dimensional aspect to the research, examining neural associations with continuous measures of irritability across diagnoses. In work being prepared for publication, we found differences between BD and DMDD in associations between irritability and amygdala and superior temporal gyrus activation, suggesting that the circuitry mediating irritability may not be the same across diagnoses. This emphasizes the potential importance of integrating both categorical (i.e., diagnostic group) and dimensional (e.g., irritability) approaches into research on psychiatric illness. A major focus of our work continues to be treatment. We have continued our double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor (SRI) antidepressant that is effective in the treatment of pediatric anxiety) plus stimulant is more effective than placebo plus stimulant in the treatment of severe irritability in youth. Importantly, stimulant and SRI treatment tend to have a lower side-effect burden than the atypical antipsychotic treatment that is considered first-line treatment for bipolar disorder, yet stimulants and SRI's are relatively contraindicated in patients with bipolar disorder because of concern about possibly inducing a manic episode. Therefore, this treatment trial has considerable public health importance. Thus far, we have randomized approximately 50 children into the trial, and youth are tolerating the experimental treatment well. We are also now extending our treatment work to include the development and testing of two novel psychosocial approaches to the treatment of irritability in youth. The first intervention involves computer-based training designed to shift a subject's perception of ambiguous faces from angry toward happy. This work is based on our prior work demonstrating face emotion labeling deficits in youth with SMD, and work by our collaborators showing that such face labeling training can be associated with decreases in trait anger and irritability. We first demonstrated that youth with DMDD are more likely than healthy youth to judge ambiguous faces as angry rather than happy. We then demonstrated in both healthy youth and those with DMDD that we can change this judgment through computer-based training and that, in patients with DMDD, this shift in judgment is associated with decreased irritability. However, this work in DMDD was an open trial, without a control condition. We recently received permission to conduct a controlled trial of this new Interpretation Bias Treatment, along with brain imaging before and after training. In addition, we received permission to develop a cognitive behavioral treatment designed specifically to target irritability. Unlike other available treatments, this would have a strong emphasis on behavioral techniques i.e., exposing the child to tolerable, but frustrating situations, to improve the childs ability to tolerate such situations. The design of this treatment will be based on a neuroscience-based model of irritability that we devised, based in part on hypothesized deficits that irritable children have in the process and content of instrumental learning. We are developing neuroimaging paradigms that can be used pre- and post- treatment to document changes in the circuitry mediating these processes during successful treatment.